HEDGEHOG INHIBITORS

• US 20130012513A1
• Filed: 01/06/2011
• Published: 01/10/2013
• Est. Priority Date: 01/07/2010
• Status: Active Grant

• Current Assignee: Anthony Pinkerton, Jean-Michel Vernier, John May, Patrick O'Connor, Pierre-Yves Bounaud, Stephanie Hopkins, William Ripka
• Original Assignee: Selexagen Therapeutics, Inc.
• Inventors: Vernier, Jean-Michel, Ripka, William, Pinkerton, Anthony, Bounaud, Pierre-Yves, Hopkins, Stephanie, May, John, O'Connor, Patrick
• Granted Patent: US 9,174,949 B2
• Time in Patent Office: Days
• US Class Current: 514/236.8
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Described herein are compounds, pharmaceutical compositions and methods for the inhibition of Hedgehog signaling. Said compounds, pharmaceutical compositions and methods have utility in the treatment of human and veterinary disease and disorders.

Claims

1. A compound having the structure of Formula (I):

2. The compound of claim 1 wherein X is —

S—

, or —

O—

.

3. The compound of claim 1 wherein G¹ and G² cannot both be hydrogen.

4. The compound of claim 1 wherein:

X is —

S—

, —

O—

, —

N(H)—

or —

N(R¹)—

;

Y is halogen, C₁-C₃ alkyl, —

CN, or —

CF₃;

n is 0, 1, 2 or 3;

G¹ is hydrogen, halogen, C₁-C₃ alkyl, —

CN, or —

CF₃;

G² is hydrogen, halogen, C₁-C₃ alkyl, —

CN, or —

CF₃, and wherein G¹ and G² cannot both be hydrogen;

R¹ is H or C₁-C₃ alkyl;

R² is selected from halogen, —

CN, alkyl, aryl, —

O-aryl, —

O-heteroaryl, —

CH₂-aryl, —

CH₂-heteroaryl, —

NH-aryl, —

SO₂-aryl, —

NH-heteroaryl, —

NH-alkyl, —

CH₂—

NH-alkyl, —

CH₂—

N(alkyl)₂, —

CH₂—

(N-linked heterocycle), —

CH₂—

(C-linked heterocycle), N-linked heterocycle, and C-linked heterocycle;

R⁴ is selected from alkoxy, —

CN, —

SO₂-alkyl, —

SO₂NH₂, —

NHSO₂-alkyl, —

NHSO₂-aryl, —

NHCO-alkyl, —

NHCO-aryl, —

NHCONH-alkyl, —

NHCONH-aryl, —

CONH₂, —

CONH-alkyl, —

CONH-aryl, —

CON(alkyl)₂, —

CON(aryl)₂, —

CO₂H, and —

CO₂alkyl; and

R³, R⁵ and R⁶ are each independently selected from hydrogen, halogen, —

CN, alkyl, aryl, heteroaryl, C-linked heterocycle, —

O-alkyl, —

O-aryl, —

O-heteroaryl, N-linked heterocycle, —

NH-alkyl, —

N(alkyl)₂, —

NH-aryl, —

NHheteroaryl, —

CO₂H, —

CO₂alkyl, —

SO₂alkyl, —

SO₂NH₂, —

SO₂NHalkyl, —

SO₂N(alkyl)₂, —

NHSO₂alkyl, —

NHSO₂aryl, —

NHCONH-alkyl, —

NHCON(alkyl)₂, —

N(alkyl)CONH₂, —

N(alkyl)CONH(alkyl), and —

N(alkyl)CON(alkyl)₂.

5. The compound of claim 1 wherein n is 0.

6. The compound of claim 1 wherein n is 1.

7. The compound of claim 1 wherein G² is H.

8. The compound of claim 1 wherein G² is H and G¹ is alkyl.

9. The compound of claim 1 wherein X is —

S—

.

10. The compound of claim 1 wherein R² is —

CH₂—

NH-alkyl, —

CH₂—

N(alkyl)₂, —

CH₂—

(N-linked heterocycle), or —

CH₂—

(C-linked heterocycle).

11. The compound of claim 1 wherein R² is halogen, —

CN, -alkyl, or —

CF₃.

12. The compound of claim 1 wherein R⁴ is —

SO₂Me or —

OMe.

13. The compound of claim 1 wherein R² is halogen and R⁴ is —

SO₂Me.

14. The compound of claim 1 wherein R² is halogen and R⁴ is —

OMe.

15. The compound of claim 1 wherein n is 0;

G² is H;

G¹ is alkyl;

X is —

S—

;

R² is halogen and R⁴ is —

OMe.

16. The compound of claim 1 wherein n is 0;

G² is H;

G¹ is alkyl;

X is —

S—

;

R² is halogen and R⁴ is —

SO₂Me.

17. A pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of Formula (I) has the following structure:

18. A method of inhibiting the Hedgehog pathway in a cell comprising contacting the cell with an inhibitory concentration of a compound of Formula (I):

23. The method of claim 18, wherein the cell is characterized by a smoothened gain-of-function phenotype.

24. The method of claim 18, wherein the cell is characterized by a constitutively active smoothened phenotype.

19. (canceled)

20. (canceled)

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22. (canceled)

25. (canceled)

26. (canceled)

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31. (canceled)

32. (canceled)